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OK. We are wrapping up our segment
on genetics today,
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Genetics 4. We're going to talk
about human disease genetics,
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modes of inheritance for human
diseased genes.
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And then we'll transition next time
into molecular biology,
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which is the next blank square here.
And then recombinant DNA cell
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biology and beyond.
I wanted to start today by clearing
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up a couple of things.
Firstly, the term F1,
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in the last lecture I gave you a
list of terms,
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and I used this definition of the
first filial generation,
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the F1 generation as the product of
crosses between two homozygous
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individuals, homozygous for
different alleles such that the
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offspring were always heterozygous,
big A, little A at that particular
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gene.
Well, it turns out that some people
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use the term F1 to refer to the
offspring of any cross.
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So you have the parents and you
have the F1s regardless of the
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genotype of the parents.
So that's a looser definition of
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the term F1. And it's been used in
Section and so on,
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so I didn't want to confuse you.
The strict definition is the one I
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told you, but don't get hung up on
that. We're always going to give
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you the relevant genotypes so you'll
be able to figure out what the
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genotypes of the offspring are.
Also, near the end of the last
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lecture, I talked about crosses
involving linked genes.
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If you remember the Y and D gene
controlling color and density,
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I think, of peas. And I told you
that they were linked,
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and we carried out a test cross.
And we then worked out what the
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percentages of the different
phenotypes and genotypes would be.
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Well, in that example,
I assumed that the Y allele and the
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D allele were together on the same
chromosome. But importantly if
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you're just given the genotype as
it's written here,
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you actually cannot know that.
The big Y might be on the opposite
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chromosome from the big D.
So to avoid confusion about that
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sort of thing,
in future examples and in problems,
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problems, that is test questions,
we'll always show you the
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chromosomes so you'll know that the
genes are together on the same
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chromosome or on opposite.
Yeah. And in the absence of this,
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if the question is to tell us what
the alleles must look like and they
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give you the phenotype,
you have to conclude the genotype.
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If the question is tell us what the
alleles must look like then we're
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not going to give you the answer,
but in other situations where
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there's ambiguity about what the
alignment might be, we'll
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tell you what that is.
OK? We also had a question from a
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student, actually an emailed
question, those are also welcome,
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email question from a student. It
was good question because in our
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discussion of dominance and
recessiveness,
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we really haven't dealt with the
molecular nature of that.
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And that was this individual's
interest. Why is an allele dominant
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over another one?
Why is a trait dominant over
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another one?
And I gave an example to him,
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which I will give to you, which I
think covers most of the examples
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that we've been discussing in class.
And it also is an opportunity for
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me to reinforce the notions related
to chromosomes,
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genes, DNA and proteins,
because apparently there are some of
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you who are still a little fuzzy on
those relationships.
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So let's imagine a gene which is
present on a chromosome.
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Chromosome shown here. Gene shown
here. And it's the S gene that
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we've talked about before that
controls smooth versus
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wrinkled pea texture.
So here's the S gene.
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It's made up of DNA. And based on
the sequence of that DNA within the
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gene, therein lies the information
to produce a protein.
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And we're going to call this
protein, in our example,
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this is a hypothetical example,
the starch synthase protein. It's
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an enzyme that controls a reaction,
that catalyzes a reaction from some
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sugar substrate into some starch.
And if you make enough of that
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starch product then you
have a smooth shape.
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OK? This enzyme controls shape
because it produces this product
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which is involved in the shape of a
pea. OK? So this is the normal
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situation. The big S allele
produces a functional starch
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synthase enzyme which produces
enough product to give the pea its
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smooth shape. In this example,
the little S allele, which is the
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recessive one,
has a mutation within the coding
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sequence of the gene.
We won't talk about the nature of
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that mutation just yet,
what it is, why it causes what it
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does because you're going to get
that in the next segment.
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Just suffice to say that it's a
mutation, an alteration of the DNA
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such that the protein that's
produced from this allele is
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nonfunctional.
You might be able to see I've
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inserted a little X there.
It's actually quite little and
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invisible on your handout,
but you might want to just circle it
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if you look carefully.
There's a little X there which is
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the result of this mutation.
And that X causes the protein to be
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nonfunctional.
The enzyme now does not catalyze
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the production of this starch
product, so no starch product is
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produced. If you don't make the
starch product you don't have a
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smooth shape, you have a wrinkled
shape. OK? If the genotype of the
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pea is little S,
little S then none of this enzyme is
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produced such that none of the
starch product is produced such that
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the pea is wrinkled.
OK? Now what happens if you're big
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S, little S, the heterozygote?
Well, for many biochemical reactions,
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having just one copy of the gene
that encodes the functional enzyme
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is enough. For many biochemical
reactions that's true.
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And so in a situation where big S
is dominant over little S,
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we assume that having one copy of
big S makes enough of the starch
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synthase protein to make enough of
that starch product to give the pea
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its smooth shape. OK?
So that's a simple example of why
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big S is dominant over little S,
why you only see the phenotype
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associated with the little S allele,
the wrinkled phenotype when you have
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two copies of the little S allele.
OK? So I hope that helps clarify
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the situation for you and actually
is useful as we talk about human
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disease genes as well.
So this is a slide from your book
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which allows us to transition from
concepts of inheritance
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to real-life stuff.
Genes that regulate how your body
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functions normally or in response to
various environmental stresses.
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We're now in an era where we can
relatively easily figure out whether
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a disease has a genetic component by
looking at families that might have
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that disease, and based on that
information and using mapping
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techniques like I described to you
last time, we can isolate where that
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gene might lie on all
of your chromosomes.
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And then using molecular techniques,
which we'll talk about in future
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lectures, we can actually isolate
that gene, determine its sequence,
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and based on that produce lots of
various valuable things like better
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ways to diagnose the disease,
better ways to understand how the
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disease process takes place such
that we can then perhaps prevent the
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disease from occurring in the first
place or treating it more
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effectively by replacing the gene
with a new copy or producing a drug
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that can replace the
gene in other ways.
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So this is what we're after.
So we need to understand diseased
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genes and how they behave in such
affected families.
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So there are a number of diseases
which have a genetic component.
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And these diseases have various
modes of inheritance.
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Some of them are autosomal dominant.
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The diseased gene is dominant over
the wild type gene,
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and I'll give you examples of that.
And the term autosomal means that
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it's not sex linked.
That is the disease gene is carried
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on chromosomes 1 through 22,
one of the those chromosomes,
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not on the X or the Y.
It doesn't matter if your father,
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whether the disease gene is coming
from a male or a female,
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passed on to a daughter or a son.
There's no sex linkage for these
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autosomal dominant diseases.
There another class of genes,
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disease genes which follow autosomal
recessive inheritance patterns.
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Here the disease gene is recessive
to wild type.
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You only see the disease phenotype
when you're homozygous for the
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mutant allele.
And, again, autosomal because it's
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not sex linked.
There are X linked diseases which
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are dominant. In this case,
the disease gene is on the X
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chromosome. There are also X linked
diseases that are recessive.
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There are very few,
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but for the sake of completeness,
Y linked diseases. But there are so
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few that we're actually not going to
talk about them at all in this class.
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And, finally,
there's a class of diseases that
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we're also not going to talk about
but get inherited not from the genes
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that are in the nucleus of the cell
along your chromosomes but rather
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get inherited from the
mitochondria.
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And since we haven't talked about
mitochondria with you really at all
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we're not going to expect you to
know about those diseases,
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but just have in the back of your
minds that those are relatively
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important. Autosomal dominant
diseases are not terribly common.
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There are about 200 known.
Autosomal recessive diseases are
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actually much more common,
though not very frequent in the
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population.
There are about 2,
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00 of these known. And together I
would estimate there are about 25
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sex linked diseases.
So we've used the term autosomal
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dominant, autosomal recessive,
sex linked. What does this really
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look like in terms of the
genes and the alleles?
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Well, just as in the case of peas,
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a dominant disease allele will cause
disease regardless of the nature of
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the other allele.
It's dominant over the normal
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common version of the gene.
So if we call this allele the
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disease allele of some gene --
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-- and this allele the commonly
found on in the population,
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and we refer to these often as the
wild type --
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-- in an individual who has this
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genotype for a dominant disease gene,
will they develop disease?
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Yes, because the disease allele is
dominant over the normal copy of the
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gene. So these individuals
will develop disease.
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For recessive disease alleles you
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need to have both copies,
both alleles be mutant in order to
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manifest the disease.
So here's another gene,
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which we'll call the H gene,
which has a disease allele. This
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individual is homozygous for the
disease allele.
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Will this individual develop
disease?
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There might be other people in the
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population who are heterozygous for
that allele and have a wild type
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allele on the other chromosome.
Will they develop disease? No.
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These individuals are called
heterozygous carriers.
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They carry the disease allele,
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but because they also carry a wild
type allele they don't develop the
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disease. They're normal.
They're normal in the sense of their
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phenotype. They have an abnormal
genotype in the sense that they have
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a disease allele,
but they're normal in the sense of
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their genotype,
phenotype. Now,
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for X linked genes,
sorry, before I do that let me --
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Let me review for you sex
determination.
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We talked about this briefly.
In order to understand the
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inheritance pattern for X linked
genes you need to remember this.
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That males of course have one X
chromosome and one Y chromosome.
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Females have two X chromosomes.
If you think of a Punnett Square
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related to the inheritance of
chromosomes males will pass along an
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X or a Y at 50% each,
females will pass along one of their
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two Xs.
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Will produce an equal number of
males and females from such crosses.
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But it's important to think about
where the X chromosomes come from,
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specifically males and the Y
chromosomes.
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Males transmit their only Y,
their only Y to all of their sons.
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If you're the son then you've
gotten your father's only Y.
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Males transmit their only X
chromosome to all of
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their daughters.
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If you're the daughter,
when you're the daughter of a male,
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you have inherited his X chromosome.
OK?
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Females transmit either X to each
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daughter or son.
In the case of the female X,
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you can be a male who got this X
chromosome or a male who got this X
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chromosome. You can be a female who
got this X chromosome or a female
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who got this X chromosome.
And that's important for
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understanding the disease genetics.
So let's imagine a dominant disease
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involving the X chromosome.
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A gene, we'll call it Q.
Males only have one X chromosome.
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They only have one X chromosome,
therefore if they carry the disease
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gene they're going
to get disease.
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Females have two X chromosomes.
They might carry the disease allele
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on one but a normal copy on the
other. In this scenario,
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will they develop disease?
Yes, because it's a dominant
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disease allele.
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For recessive X linked disease,
once again, males only have one X.
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Are they going to get disease? Yes.
Females have two X chromosomes.
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If they carry a disease allele on
one they are likely to carry a wild
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type copy on the other.
Are they going to get disease?
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No. They're going to be
heterozygous carriers.
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And you'll see how this plays out
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towards the end of the lecture.
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OK. So let's look at some examples.
We're going to start with recessive
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diseases first,
recessive autosomal diseases first.
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And one you've already seen before,
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and that's PKU, phenylketonuria. If
you recall, this is a disease which
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is associated with failure to make
an enzyme that converts
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phenylalanine to tyrosine.
It's an enzyme called phenylalanine
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hydroxylase. If you don't have that
enzyme then you produce too much of
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this byproduct,
phenylpyruvic acid which is toxic
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and leads to brain damage
and retardation.
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This can be avoided,
the disease can be avoided by
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limiting your amount of dietary
phenylalanine.
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And that's why such patients are
not supposed to have Equal,
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as we discussed before. The disease,
PKU, is autosomal recessive.
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The incidence is rare, about one in
10,000 to 15,000 individuals have
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PKU. As I talked to you about last
time, the mutant allele has a single
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amino acid chain change in the
active site of this enzyme which
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changes an arginine residue to a
tryptophan residue.
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And that makes the enzyme inactive.
This is an autosomal recessive
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disease. So if you have one mutant
allele and one normal copy of the
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phenylalanine hydroxylase gene,
do you have the disease? No. You
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would be a carrier but you would not
have the disease symptoms.
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Because again, as in the other
hypothetical example,
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most of the time, if you have a
single normal copy of an enzyme that
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carries out some biochemical
reaction that's enough and your
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phenotype is normal.
Here's another common example,
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cystic fibrosis. This is actually a
more common disease.
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It affects about one in 2,
00 to 3,000 individuals. That's not
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an insignificant number.
So there are a lot of people with
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cystic fibrosis in this country.
Again, it's autosomal recessive.
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Patients present with the disease
at birth.
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They have problems both in their
intestinal system as well as in
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their lungs. It tends to be the
lung symptoms that ultimately kills
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the patient due to inability to
breathe properly,
253
00:21:11 --> 00:21:15
but actually more importantly
persistent infections which
254
00:21:15 --> 00:21:19
ultimately are so severe that they
lead to death.
255
00:21:19 --> 00:21:23
And these patients tend to die
within the first two to three
256
00:21:23 --> 00:21:27
decades of life.
The gene encoded by the disease,
257
00:21:27 --> 00:21:31
the gene responsible for this
disease is a chloride channel.
258
00:21:31 --> 00:21:34
When it functions properly it allows
chloride ions to move through,
259
00:21:34 --> 00:21:38
and this achieves a proper water
balance inside the cells.
260
00:21:38 --> 00:21:41
When the disease allele is present
in both copies,
261
00:21:41 --> 00:21:45
this channel is not formed properly,
and therefore the water balance in
262
00:21:45 --> 00:21:49
such cells is not correct and it
leads to the build up of this kind
263
00:21:49 --> 00:21:52
of mucousy sticky substance both in
the lungs and in the intestines.
264
00:21:52 --> 00:21:56
These individuals, as you can see,
have a very hard time breathing, and
265
00:21:56 --> 00:22:00
they have to get this mucous cleared
from their lungs periodically.
266
00:22:00 --> 00:22:04
And they also often have to have
respirators to allow them to breath.
267
00:22:04 --> 00:22:08
OK. So that's some examples of
autosomal recessive diseases.
268
00:22:08 --> 00:22:13
Let's think about the genetics.
And we'll talk about CF
269
00:22:13 --> 00:22:17
specifically. Let's imagine the
disease allele of CF.
270
00:22:17 --> 00:22:22
We'll call it CFD. There are
actually many different disease
271
00:22:22 --> 00:22:26
alleles for this disease,
but we'll just lump them together.
272
00:22:26 --> 00:22:33
Here are two individuals with this
273
00:22:33 --> 00:22:41
genotype. Do these individuals
manifest the disease?
274
00:22:41 --> 00:22:49
Yes or no? Do they manifest the
disease? No, because this is an
275
00:22:49 --> 00:22:58
autosomal recessive disease and they
have a wild type copy.
276
00:22:58 --> 00:23:03
But if we think about the offspring
that they could produce,
277
00:23:03 --> 00:23:09
this individual will produce gametes
that carry the D allele and the wild
278
00:23:09 --> 00:23:15
type allele, likewise this
individual, the D allele and the
279
00:23:15 --> 00:23:21
wild type allele,
such that the offspring will either
280
00:23:21 --> 00:23:27
be DD, wild type D,
wild type, wild type or wild type,
281
00:23:27 --> 00:23:32
D. Right?
So you'll have one wild type,
282
00:23:32 --> 00:23:37
wild type individual produced out of
such a cross. And this individual
283
00:23:37 --> 00:23:42
now has no disease allele present.
This individual is both
284
00:23:42 --> 00:23:47
genotypically and phenotypically
normal. No more issues about cystic
285
00:23:47 --> 00:23:52
fibrosis for this person or his or
her descendants.
286
00:23:52 --> 00:23:57
There will be two individuals who
are heterozygous,
287
00:23:57 --> 00:24:02
and these individuals are carriers.
They don't have the disease but they
288
00:24:02 --> 00:24:07
do have a mutant allele.
So depending on whom they marry,
289
00:24:07 --> 00:24:12
I shouldn't generalize, depending on
whom they have children with they
290
00:24:12 --> 00:24:17
may or may not have to worry about
the fact that they have a mutant CF
291
00:24:17 --> 00:24:22
allele. And one,
on average, out of four will have
292
00:24:22 --> 00:24:28
two disease alleles and
develop CF. OK?
293
00:24:28 --> 00:24:38
So we're going to now think about
294
00:24:38 --> 00:24:42
these diseases in inheritance
looking at pedigrees,
295
00:24:42 --> 00:24:46
which I think are probably familiar
to most of you.
296
00:24:46 --> 00:24:50
They're described in your book as
well. But I just want to make sure
297
00:24:50 --> 00:24:54
you understand what the symbols mean
before we get into it.
298
00:24:54 --> 00:24:58
Females are represented as circles.
Males are represented as squares.
299
00:24:58 --> 00:25:03
Seems appropriate.
Lines between them represent a
300
00:25:03 --> 00:25:09
mating, they have mated.
And the offspring are represented
301
00:25:09 --> 00:25:21
below.
302
00:25:21 --> 00:25:27
If the symbol is left open then the
individual is normal,
303
00:25:27 --> 00:25:34
genotypically and phenotypically.
If the individual has a shaded
304
00:25:34 --> 00:25:41
symbol they are affected,
they show disease symptoms.
305
00:25:41 --> 00:25:48
And if the symbol is partially
shaded, I usually fill in half the
306
00:25:48 --> 00:25:55
symbol, the book will sometimes put
a little circle inside the circle
307
00:25:55 --> 00:26:02
then they are carriers.
They're heterozygous carriers.
308
00:26:02 --> 00:26:07
OK? So let's look and think about
this example up here.
309
00:26:07 --> 00:26:13
We talked about two individuals who
were both heterozygous for the
310
00:26:13 --> 00:26:19
disease allele,
so they were carriers.
311
00:26:19 --> 00:26:25
Their genotype was CFD,
CF wild type.
312
00:26:25 --> 00:26:32
They mated. They had
313
00:26:32 --> 00:26:42
four children.
314
00:26:42 --> 00:26:46
There were four possible genotypes,
rather three possible genotypes.
315
00:26:46 --> 00:26:51
And, in fact, we observe all three
genotypes in this generation.
316
00:26:51 --> 00:26:55
We have one individual over here who
doesn't have her symbol filled.
317
00:26:55 --> 00:27:00
We have another whose symbol is
fully filled.
318
00:27:00 --> 00:27:08
And then we have two whose symbols
are partially filled.
319
00:27:08 --> 00:27:16
What's the genotype of this
individual? Wild type,
320
00:27:16 --> 00:27:24
wild type. This one? D,
D. This one? D, wild type.
321
00:27:24 --> 00:27:32
And this one? Same thing. OK?
So that's what pedigrees look like.
322
00:27:32 --> 00:27:37
Let me show you a larger pedigree
and give you some of the rules that
323
00:27:37 --> 00:27:43
apply to autosomal recessive
diseases. So here's a large
324
00:27:43 --> 00:27:49
pedigree involving an autosomal
recessive gene,
325
00:27:49 --> 00:27:55
disease gene. Again,
the two parents are heterozygous.
326
00:27:55 --> 00:28:01
They had many, many offspring all
here. Roughly a quarter of them
327
00:28:01 --> 00:28:07
will carry both copies of the
disease gene and develop disease.
328
00:28:07 --> 00:28:11
Among the rest there will be
unaffected individuals but of two
329
00:28:11 --> 00:28:16
classes, ones that don't have the
disease gene at all and ones who are
330
00:28:16 --> 00:28:20
heterozygous carriers.
Two-thirds of those unaffected
331
00:28:20 --> 00:28:25
offspring are themselves carriers,
two-thirds. Two-thirds of the
332
00:28:25 --> 00:28:30
unaffected offspring are
themselves carriers.
333
00:28:30 --> 00:28:34
Among those half of the offspring of
a carrier are themselves carriers,
334
00:28:34 --> 00:28:39
as shown here. So if this
individual came to you at a genetics
335
00:28:39 --> 00:28:44
clinic and wanted to know what is my
likelihood of carrying the D mutant
336
00:28:44 --> 00:28:49
allele, you'd be able to say,
without knowing the genotype of his
337
00:28:49 --> 00:28:54
mother you would be able to say that
it's half of a half
338
00:28:54 --> 00:28:58
or a quarter. OK?
Now, every once in a while two
339
00:28:58 --> 00:29:02
affected individuals,
two homozygotes have children,
340
00:29:02 --> 00:29:06
as shown here. And you can see in
that scenario all of the offspring
341
00:29:06 --> 00:29:09
have disease because the only
alleles that are present are the
342
00:29:09 --> 00:29:13
mutant alleles.
That has to be true because these
343
00:29:13 --> 00:29:17
are both affected,
and therefore all of the offspring
344
00:29:17 --> 00:29:21
will also only inherit mutant
alleles and develop the disease
345
00:29:21 --> 00:29:25
themselves. OK?
And importantly because the disease
346
00:29:25 --> 00:29:31
gene is coming in on chromosomes 1
to 22, one of those and not the X or
347
00:29:31 --> 00:29:37
the Y, there is no gender
associations here.
348
00:29:37 --> 00:29:43
Mothers can pass the disease to
their daughters and their sons.
349
00:29:43 --> 00:29:49
Fathers can pass the disease to
their daughters and their sons.
350
00:29:49 --> 00:29:55
There are no gender associations
with this scenario.
351
00:29:55 --> 00:29:58
OK. Disease alleles are present in
different frequencies in the
352
00:29:58 --> 00:30:02
population. Some of them are
extremely rare,
353
00:30:02 --> 00:30:06
but some of them are actually rather
common.
354
00:30:06 --> 00:30:16
So we're talking about the allele
355
00:30:16 --> 00:30:21
frequency, the percentage of alleles
among all of our chromosomes that
356
00:30:21 --> 00:30:27
are the disease type.
For PKU it depends a lot on where
357
00:30:27 --> 00:30:34
you're from.
For example, in Turkey it's actually
358
00:30:34 --> 00:30:42
rather common,
one in 206,000 alleles of this gene
359
00:30:42 --> 00:30:51
are mutant in this population,
but in Japan it's much less common.
360
00:30:51 --> 00:31:00
One in 220,000 Japanese carry this
allele.
361
00:31:00 --> 00:31:04
Exactly why this is we're not
entirely sure,
362
00:31:04 --> 00:31:08
although I'll give you some
speculation in a little while about
363
00:31:08 --> 00:31:13
what controls the frequency of these
actually rather deleterious alleles.
364
00:31:13 --> 00:31:17
CF is fairly frequent. One in 25
alleles are CF.
365
00:31:17 --> 00:31:22
One in 25. There are as maybe 200
of you in this room,
366
00:31:22 --> 00:31:26
so that's some number of mutant
alleles among you. It's
367
00:31:26 --> 00:31:31
a fairly high number.
You're sitting there carrying a
368
00:31:31 --> 00:31:37
mutant copy of the CF allele.
This is actually relevant to
369
00:31:37 --> 00:31:42
European descendancy.
I'm not entirely sure whether it
370
00:31:42 --> 00:31:48
applies to all descendencies but
let's just say that it's roughly
371
00:31:48 --> 00:31:53
that number. And another disease
that you might have heard of
372
00:31:53 --> 00:31:59
Tay-Sachs disease in the Ashkenazi
Jewish population --
373
00:31:59 --> 00:32:08
-- is also quite common.
374
00:32:08 --> 00:32:13
One in 25. It's so common,
in fact, that in certain parts of
375
00:32:13 --> 00:32:19
the world individuals undergo
genetic testing before they decide
376
00:32:19 --> 00:32:24
whom to date because they want to
avoid the risk that they're going to
377
00:32:24 --> 00:32:30
date somebody else who carries
such a mutation.
378
00:32:30 --> 00:32:33
This is actually a very horrible
disease. I shouldn't joke about it.
379
00:32:33 --> 00:32:37
So they want to avoid ever having
to face the problem of having a
380
00:32:37 --> 00:32:41
child who has Tay-Sachs disease.
So they undergo, in a sense,
381
00:32:41 --> 00:32:45
pre-marriage counseling to figure
out their genotype to decide whether
382
00:32:45 --> 00:32:49
or not to date.
And you can also imagine with
383
00:32:49 --> 00:32:53
similar tests we could figure out
whether or not individuals carry
384
00:32:53 --> 00:32:57
mutations in these genes to let them
know what their risks of developing
385
00:32:57 --> 00:33:01
disease are or whether or not to
maintain a pregnancy of a child who
386
00:33:01 --> 00:33:05
may or may not be affected
and so on.
387
00:33:05 --> 00:33:09
So they're very serious societal
implications for these kinds of
388
00:33:09 --> 00:33:14
disease alleles.
Now, some of the alleles are very
389
00:33:14 --> 00:33:18
rare. Here's one example in the
Japanese population of PKU.
390
00:33:18 --> 00:33:23
The likelihood that two individuals
would randomly get together who had
391
00:33:23 --> 00:33:27
mutant alleles of a phenylalanine
hydroxylase gene and have a child is
392
00:33:27 --> 00:33:32
exceedingly small.
And so in these situations,
393
00:33:32 --> 00:33:37
where the allele frequency is
extremely rare,
394
00:33:37 --> 00:33:42
when you find an affected individual
it's almost always a sure sign of
395
00:33:42 --> 00:33:47
inbreeding. Consanguinity is the
term used in genetics where cousins
396
00:33:47 --> 00:33:52
or other relatives marry and have
children. And since they are
397
00:33:52 --> 00:33:57
related and have a higher allele
frequency within their families of a
398
00:33:57 --> 00:34:02
particular allele then the
likelihood that they'll have an
399
00:34:02 --> 00:34:07
offspring who has two copies of the
allele is much higher.
400
00:34:07 --> 00:34:11
And so when you see a pattern such
as this, it's a fairly clear
401
00:34:11 --> 00:34:16
indication that you're dealing with
an autosomal recessive disease
402
00:34:16 --> 00:34:21
involving consanguineous mating.
Here are two cousins who are
403
00:34:21 --> 00:34:26
producing offspring both of whom are
affected. And when you see a
404
00:34:26 --> 00:34:31
pattern like this you can actually
figure out, or at least figure out
405
00:34:31 --> 00:34:36
pretty well who were the carriers in
this scenario,
406
00:34:36 --> 00:34:41
who were the carriers in this family.
Since both, since the children have
407
00:34:41 --> 00:34:46
two mutant copies then both of their
parents must be heterozygous
408
00:34:46 --> 00:34:50
carriers. OK?
That goes without saying.
409
00:34:50 --> 00:34:55
They're heterozygous. Since this
individual is heterozygous and the
410
00:34:55 --> 00:35:00
allele was passed on from their
grandparents then his mother must
411
00:35:00 --> 00:35:05
also carry the allele inherited from
one of the two grandparents.
412
00:35:05 --> 00:35:09
Likewise this woman's father must
carry the mutant allele.
413
00:35:09 --> 00:35:13
And in this generation we actually
don't know whether it's the male or
414
00:35:13 --> 00:35:17
the female who carries the mutation.
It could be either. And it's been
415
00:35:17 --> 00:35:22
passed along to both sides of this
family tree and reduced to
416
00:35:22 --> 00:35:26
homozygocity in this generation.
OK? You can also begin to figure
417
00:35:26 --> 00:35:30
out what the likelihood of other
members of the family tree
418
00:35:30 --> 00:35:35
is being heterozygous.
So this individual here has a one in
419
00:35:35 --> 00:35:39
two chance. One of these two parents
is definitely a heterozygote,
420
00:35:39 --> 00:35:43
and so the likelihood that he's a
heterozygote is one in two.
421
00:35:43 --> 00:35:47
And among his children you could
say they have a one in four chance.
422
00:35:47 --> 00:35:51
If he has a one in two chance then
there's a one in two chance that
423
00:35:51 --> 00:35:55
he'll pass it onto them,
so overall there's a one in four
424
00:35:55 --> 00:35:59
chance that they will be
themselves carriers.
425
00:35:59 --> 00:36:03
And this, again,
this kind of genetic testing is done
426
00:36:03 --> 00:36:07
frequently to figure out what your
relative risk of developing a
427
00:36:07 --> 00:36:11
particular disease are.
Now, as I said, for other disease
428
00:36:11 --> 00:36:16
alleles like CF and Tay-Sachs,
the allele frequency is actually
429
00:36:16 --> 00:36:20
strikingly high.
And yet if you're homozygous for
430
00:36:20 --> 00:36:24
these mutations you're dead.
Not necessarily right away but not
431
00:36:24 --> 00:36:28
for very long.
It clearly reduces your
432
00:36:28 --> 00:36:33
reproductive fitness.
And so why would these alleles be
433
00:36:33 --> 00:36:37
present in our population at all?
Why wouldn't they be removed
434
00:36:37 --> 00:36:41
through natural selection?
We're not going to get into this in
435
00:36:41 --> 00:36:45
great detail, but there are theories
out there and some evidence to
436
00:36:45 --> 00:36:49
support them that there might be
actually an advantage in certain
437
00:36:49 --> 00:36:53
circumstances for being heterozygous
wild type over mutant.
438
00:36:53 --> 00:36:57
And there are theories both related
to Tay-Sachs disease,
439
00:36:57 --> 00:37:01
sickle cell disease and cystic
fibrosis such that if you are
440
00:37:01 --> 00:37:05
heterozygous you actually survive
better in the face of certain
441
00:37:05 --> 00:37:10
pathogenic exposure than do people
who are wild type for both alleles.
442
00:37:10 --> 00:37:14
And that's the argument for why
these alleles actually built up,
443
00:37:14 --> 00:37:19
at least in the past, over the
evolution of our species.
444
00:37:19 --> 00:37:24
OK. Let's transition now to
autosomal dominant diseases.
445
00:37:24 --> 00:37:29
This is a famous example,
Huntington's disease,
446
00:37:29 --> 00:37:33
otherwise called Huntington's chorea.
Relatively rare.
447
00:37:33 --> 00:37:37
About one in 10,
00 to 25,000 individuals affected.
448
00:37:37 --> 00:37:41
It exhibits an autosomal dominant
pattern of inheritance,
449
00:37:41 --> 00:37:45
as you'll see in a moment.
The age of onset is about 35 to 40
450
00:37:45 --> 00:37:49
years of age. These individuals
actually are totally normal for the
451
00:37:49 --> 00:37:53
first three to four decades.
You wouldn't know that they had a
452
00:37:53 --> 00:37:57
disease. But starting at that time
they begin to develop symptoms which
453
00:37:57 --> 00:38:01
involve both effects on their
personalities but more importantly
454
00:38:01 --> 00:38:05
effects on their movements.
That's what you first begin to see.
455
00:38:05 --> 00:38:09
That's what chorea means. It's
sort of this dance-like movement.
456
00:38:09 --> 00:38:14
And then that gets much, much more
severe and stereotypical.
457
00:38:14 --> 00:38:18
And eventually, in addition to that,
there's death of cells in the brain.
458
00:38:18 --> 00:38:23
And the combination of these
affects leads to the death of the
459
00:38:23 --> 00:38:28
individual by about the fourth or
fifth decade of life.
460
00:38:28 --> 00:38:32
This is actually a movie of an
individual who has Huntington's
461
00:38:32 --> 00:38:37
disease.
He's being told to hold his arms
462
00:38:37 --> 00:38:41
straight out, but because of this
neurogenerative process that's
463
00:38:41 --> 00:38:46
taking place within his brain and
also other parts of his nervous
464
00:38:46 --> 00:38:50
system he's unable to do so.
And this is sort of the
465
00:38:50 --> 00:38:55
stereotypical presentation of
Huntington's chorea.
466
00:38:55 --> 00:38:59
They have this wave-like movement
and also their limbs get stuck in
467
00:38:59 --> 00:39:04
particular postures,
as you can see this individual here.
468
00:39:04 --> 00:39:07
At the molecular level the problem
in these individuals is that their
469
00:39:07 --> 00:39:11
brain cells are dying,
particular ones, actually,
470
00:39:11 --> 00:39:14
within a particular region of the
brain surrounding this ventricle
471
00:39:14 --> 00:39:18
here. And this is a normal space in
a normal brain.
472
00:39:18 --> 00:39:22
And there are various sets of
neurons on either side of those
473
00:39:22 --> 00:39:25
ventricles. And in HD patients
those cells are progressively lost
474
00:39:25 --> 00:39:29
over time, and when those cells are
lost you lose motor control and you
475
00:39:29 --> 00:39:33
also develop rather
severe dementia.
476
00:39:33 --> 00:39:37
And the reason that those cells are
being lost is that the mutant
477
00:39:37 --> 00:39:41
protein, the mutant form of this
protein called Huntington,
478
00:39:41 --> 00:39:45
the mutant form builds up inside of
those cells and aggregates and
479
00:39:45 --> 00:39:49
causes the cells to die.
OK? And this is why this is an
480
00:39:49 --> 00:39:53
autosomal dominant disease.
If you have the disease allele then
481
00:39:53 --> 00:39:57
you will get the aggregation of the
protein and you will develop
482
00:39:57 --> 00:40:07
the disease.
483
00:40:07 --> 00:40:14
So let's take another example of a
cross between an individual who is
484
00:40:14 --> 00:40:22
normal, two normal copies of HD and
an individual who has a disease
485
00:40:22 --> 00:40:30
allele and a wild type allele who is
heterozygous. Is this
486
00:40:30 --> 00:40:36
individual diseased?
He either is already or he will be
487
00:40:36 --> 00:40:40
in the case of HD.
It's an autosomal dominant disease.
488
00:40:40 --> 00:40:44
If you have the disease allele you
will develop disease.
489
00:40:44 --> 00:40:48
If we look at a Punnett Square,
this individual will always transmit
490
00:40:48 --> 00:40:53
the wild type allele,
this individual will transmit the
491
00:40:53 --> 00:40:57
mutant allele half the time the wild
type allele of the other.
492
00:40:57 --> 00:41:01
These individuals will be wild type
D, wild type D,
493
00:41:01 --> 00:41:06
wild type, wild type,
wild type, wild type.
494
00:41:06 --> 00:41:13
So you'll get half diseased,
half normal. OK? A rather
495
00:41:13 --> 00:41:21
different picture than we saw
previously. And importantly,
496
00:41:21 --> 00:41:29
as I mentioned, the presence, the
mere presence of the D allele leads
497
00:41:29 --> 00:41:37
to the production of
this toxic protein.
498
00:41:37 --> 00:41:43
And ultimately brain damage.
And that's why it's dominant.
499
00:41:43 --> 00:41:49
OK. So let's look at a pedigree of
an autosomal dominant disorder.
500
00:41:49 --> 00:41:55
Here's an affected individual, a
female who marries,
501
00:41:55 --> 00:42:02
who has children with an unaffected
male.
502
00:42:02 --> 00:42:06
They have four children.
On average half of them will
503
00:42:06 --> 00:42:10
inherit the defective allele and
therefore develop disease.
504
00:42:10 --> 00:42:14
Half of the offspring of an
affected parent will be affected.
505
00:42:14 --> 00:42:19
Importantly, the unaffected
offspring of an affected parent have
506
00:42:19 --> 00:42:23
unaffected offspring.
If you are normal, you do not
507
00:42:23 --> 00:42:27
inherit the disease allele,
you're scot-free. Your children will
508
00:42:27 --> 00:42:32
no longer have to worry
about this disease.
509
00:42:32 --> 00:42:35
But in this case,
in this individual,
510
00:42:35 --> 00:42:38
again roughly half, in this example
two-thirds of the offspring do
511
00:42:38 --> 00:42:42
develop the disease.
This is another really important
512
00:42:42 --> 00:42:45
case of genetic testing.
This guy might have wanted to know
513
00:42:45 --> 00:42:49
that he was going to develop
Huntington's disease in order to
514
00:42:49 --> 00:42:52
decide whether to have children in
the first place.
515
00:42:52 --> 00:42:55
This individual here likewise might
want to know before the disease
516
00:42:55 --> 00:42:59
actually manifested itself what
would happen in order to make
517
00:42:59 --> 00:43:02
lifestyle decisions.
Am I going to quit work and have a
518
00:43:02 --> 00:43:06
good time for the next ten years?
Because pretty soon I'm actually
519
00:43:06 --> 00:43:10
not going to be able to.
So genetic testing actually can
520
00:43:10 --> 00:43:13
make an extremely important set of
decisions for individuals affected
521
00:43:13 --> 00:43:17
in this way. And there's actually a
subtlety here,
522
00:43:17 --> 00:43:20
too. Sometimes people don't want to
know because there's actually
523
00:43:20 --> 00:43:24
nothing to be done for them.
In the case of Huntington's disease
524
00:43:24 --> 00:43:28
that's true. We don't
have a cure for it.
525
00:43:28 --> 00:43:32
So Arlo Guthrie who is the son of
Woody Guthrie,
526
00:43:32 --> 00:43:36
who died of Huntington's disease,
apparently doesn't want to know
527
00:43:36 --> 00:43:40
because if he learns that he's going
to get it he's just going to be
528
00:43:40 --> 00:43:44
depressed. If he learns that he
didn't get it he might be relieved,
529
00:43:44 --> 00:43:48
but he doesn't want to take that
chance so he's just leading life in
530
00:43:48 --> 00:43:52
hopes that he doesn't have the
disease allele.
531
00:43:52 --> 00:43:56
Now, I actually don't know in his
case whether he has children or not.
532
00:43:56 --> 00:44:00
He has children, so he actually
made that decision almost for his
533
00:44:00 --> 00:44:04
children as well.
So important implications for these
534
00:44:04 --> 00:44:09
kinds of genetic diseases.
Now, here's an interesting pattern
535
00:44:09 --> 00:44:14
that I want to share with you.
And this relates to a phenomenon
536
00:44:14 --> 00:44:30
called penetrance.
537
00:44:30 --> 00:44:34
Penetrance. Penetrance is a number
which reflects the percentage of
538
00:44:34 --> 00:44:38
individuals who have the disease
genotype who end up getting the
539
00:44:38 --> 00:44:43
disease. I've been telling you
about examples where that's 100%.
540
00:44:43 --> 00:44:47
If you have the disease genotype
you get the disease.
541
00:44:47 --> 00:44:51
But that's not always true.
Sometimes you can have the disease
542
00:44:51 --> 00:44:56
genotype, but because of other
factors like environmental factors,
543
00:44:56 --> 00:45:00
what you eat, what you get exposed
to you actually don't
544
00:45:00 --> 00:45:05
develop the disease.
Or maybe you just got lucky because
545
00:45:05 --> 00:45:09
some of these diseases are
stochastic in nature.
546
00:45:09 --> 00:45:13
And you might have been one of the
lucky ones. That would be an
547
00:45:13 --> 00:45:17
example of lack of penetrance.
You have the disease genotype but
548
00:45:17 --> 00:45:21
you don't have the disease itself.
And this can lead to the
549
00:45:21 --> 00:45:25
development of individuals in
pedigrees, such as the one I'm going
550
00:45:25 --> 00:45:30
to show you, who are obligate
carriers, obligate carriers.
551
00:45:30 --> 00:45:34
We call them obligate carriers
because they have a child who is
552
00:45:34 --> 00:45:39
affected but they themselves were
not affected. And they have a
553
00:45:39 --> 00:45:43
parent who likewise was affected.
So the simplest explanation for a
554
00:45:43 --> 00:45:48
pedigree such as this is that this
mother passed along the disease
555
00:45:48 --> 00:45:52
allele to her daughter but she did
not manifest the disease,
556
00:45:52 --> 00:45:57
an example of lack of penetrance,
but she still had the disease allele
557
00:45:57 --> 00:46:02
which she passed onto her daughter
who developed disease.
558
00:46:02 --> 00:46:05
OK? And we call these individuals
obligate carriers.
559
00:46:05 --> 00:46:09
Even though they don't manifest the
disease they must be carriers.
560
00:46:09 --> 00:46:12
And in that sense this circle
should be shaded.
561
00:46:12 --> 00:46:16
We haven't shaded it because
actually there are other
562
00:46:16 --> 00:46:20
explanations for how you can get
this pattern. Sometimes,
563
00:46:20 --> 00:46:23
for example, the disease is such
that there are non-familial forms of
564
00:46:23 --> 00:46:27
the disease which complicate the
analysis. Heart disease is a good
565
00:46:27 --> 00:46:31
example. There are familial forms
of heart disease and there is
566
00:46:31 --> 00:46:34
sporadic heart disease.
Maybe this woman doesn't have the
567
00:46:34 --> 00:46:38
predisposing mutation and her
daughter just developed heart
568
00:46:38 --> 00:46:42
disease. That can happen.
Another example is that maybe she
569
00:46:42 --> 00:46:45
picked up a new mutation.
Her mother is actually clean but
570
00:46:45 --> 00:46:49
she picked up her own mutation in
the development of the sperm or egg
571
00:46:49 --> 00:46:53
that gave rise to her,
and then she has the disease.
572
00:46:53 --> 00:46:57
That would be rare but not
unprecedented.
573
00:46:57 --> 00:47:01
And the final example,
which is the most interesting,
574
00:47:01 --> 00:47:05
is so-called non-paternity or even
non-maternity.
575
00:47:05 --> 00:47:09
So we're making an assumption here
based on what the family has
576
00:47:09 --> 00:47:13
provided us in terms of this
pedigree that this girl is the
577
00:47:13 --> 00:47:17
daughter of this mating,
this woman and this man. But about
578
00:47:17 --> 00:47:21
10% of kids born in this country
actually have a father who isn't
579
00:47:21 --> 00:47:25
their father. It's a shocking
statistic, I know,
580
00:47:25 --> 00:47:29
but it's true. This is called
non-paternity.
581
00:47:29 --> 00:47:34
So it might be the case that this
woman actually doesn't have the
582
00:47:34 --> 00:47:40
mutation. It's just that her father,
her mate, the father of this girl
583
00:47:40 --> 00:47:45
[LAUGHTER] is not that guy.
And this is sick but true, most
584
00:47:45 --> 00:47:51
often in situations like this it's
Uncle Bob or brother Steve.
585
00:47:51 --> 00:47:57
I know it's disgusting but this is
often an example,
586
00:47:57 --> 00:48:03
the explanation for examples such as
this.
587
00:48:03 --> 00:48:07
And another interesting example is
non-maternity.
588
00:48:07 --> 00:48:12
We're assuming that this is the
mother of this child but sometimes
589
00:48:12 --> 00:48:16
families don't want to admit,
for example, that this girl had a
590
00:48:16 --> 00:48:21
baby. And so they give it to Aunt
Sue. And now Aunt Sue's child gets
591
00:48:21 --> 00:48:25
the disease, but it's not because of
Aunt Sue's genes.
592
00:48:25 --> 00:48:30
It's because of her cousin.
OK? So here are some examples.
593
00:48:30 --> 00:48:33
Now, I have one more minute,
and I need to riffle through the
594
00:48:33 --> 00:48:37
slides because I'm going to leave
you for a few days.
595
00:48:37 --> 00:48:40
And I want to just remind you that
there are X linked diseases that
596
00:48:40 --> 00:48:44
affect, that are both dominant and
recessive. Most of them are
597
00:48:44 --> 00:48:48
recessive. And here's a classic
example, an X linked recessive
598
00:48:48 --> 00:48:51
disease involving hemophilia in the
royal families of Europe.
599
00:48:51 --> 00:48:55
Importantly, when you look at X
linked disease pedigrees,
600
00:48:55 --> 00:48:58
and here's Duchenne muscular
dystrophy, another familiar disease,
601
00:48:58 --> 00:49:02
again X linked recessive, there are
certain rules that dictate the
602
00:49:02 --> 00:49:06
development of the disease
over the generations.
603
00:49:06 --> 00:49:10
They're summarized here.
And you should look in your book
604
00:49:10 --> 00:49:15
for more information.
And, finally, there are rare
605
00:49:15 --> 00:49:19
examples of X linked dominant
diseases, and their rules of
606
00:49:19 --> 00:49:24
inheritance are somewhat different.
So you should familiarize yourself
607
00:49:24 --> 00:49:27
with X linked modes of inheritance.